The ASCT2 (SLC1A5) transporter is a transporter of neutral amino acids such as glutamine and a range of other neutral amino acids (such as glutamine, leucine, and isoleucine) in and out of a cell in a Na+ dependent, obligate amino acid exchange process. These transporters, by shuttling of various amino acids across the cell membrane, may facilitate or regulate various physiological processes such as cell growth, proliferation, or even glutamatergic neurotransmission via the glutamate/glutamine cycle.
Emerging evidence implicates oncogenic signaling pathways with nutrient uptake in cancer cells. The natural amino acid glutamine is essential for cell growth and proliferation. In addition to glucose, cancer cells utilize glutamine as a carbon source for ATP production and biosynthesis. Mammalian cells internalize glutamine through an evolutionary redundant repertoire of cell surface transporters though a primary sodium-dependent transporter of glutamine. ASCT2 (gene symbol SLC1A5), stands out as a promising target for probe development. In cancer cells, SLC1A5 expression is associated with oncogenic MYC and KRAS, suggesting its relevance in many clinically important tumors, including lung, colon, and pancreas. It has been previously demonstrated that that SLC1A5 antisense RNA triggered apoptosis in human hepatocellular carcinoma cells. See Fuchs et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286(3), G467-G478. Similarly, it has been reported that SLC1A5 was expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors. Further, siRNA down regulation of ASCT2 in lung cancer cells resulted in significant growth inhibition. See Hassanein et al., Clin. Cancer Res. 2013, 19(3), 560-570. Collectively, these studies suggest that the discovery of small molecules capable of inhibiting ASCT2 activity represents an important area in the development of precision cancer medicines.
Accordingly, ASCT2 inhibitors, can be used as pharmacologic research tools to inhibit and investigate ASCT2-mediated amino acid transport and function. Such inhibitors can be used as chemotherapeutic agents alone or in combination with other chemotherapeutic agents to treat various human or mammalian tumors or cancers. These compounds can be used as anti-metabolite agents alone or in combination with other chemotherapeutic agents to slow or prevent growth of various human or mammalian tumors and they can serve as effective anti-microbial agents to suppress growth of various pathogenic microbes.
Unfortunately, few pharmacological inhibitors of ASCT2 have been reported. In 2004, Esslinger described L-γ-glutamyl-p-nitroanilide (GPNA) as a commercially available probe of the ASCT2 amino acid binding site. While this work describes potential electronic requirements for binding to ASCT2 through alteration of the amide N—H pKa via simple aryl substitutions, it did not address the steric requirements for binding to ASCT2 within this compound class.
Thus, a need remains for additional inhibitors of ASCT transporters that can be used as pharmacologic tools to evaluate the physiologic significance of the ASCT transporter by pharmacologic intervention and thus better understand its role in various biologic pathways.